EP0393109A1 - Novel 2,3-thiomorpholinedione-2-oxime derivatives, pharmaceutical compositions containing them and process for preparing same. - Google Patents

Novel 2,3-thiomorpholinedione-2-oxime derivatives, pharmaceutical compositions containing them and process for preparing same.

Info

Publication number
EP0393109A1
EP0393109A1 EP89900294A EP89900294A EP0393109A1 EP 0393109 A1 EP0393109 A1 EP 0393109A1 EP 89900294 A EP89900294 A EP 89900294A EP 89900294 A EP89900294 A EP 89900294A EP 0393109 A1 EP0393109 A1 EP 0393109A1
Authority
EP
European Patent Office
Prior art keywords
group
alkyl
alkoxy
halogen
substituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP89900294A
Other languages
German (de)
French (fr)
Other versions
EP0393109B1 (en
Inventor
Istvan Szabadkai
Kalman Harsanyi
Agnes Lampert
Gyoergy Domany
Bela Hegedues
Elemer Ezer
Judit Matuz
Katalin Saghy
Laszlo Szporny
S Gyoergy Haj
Krisztina Szekely
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Richter Gedeon Vegyeszeti Gyar Nyrt
Original Assignee
Richter Gedeon Vegyeszeti Gyar RT
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Richter Gedeon Vegyeszeti Gyar RT filed Critical Richter Gedeon Vegyeszeti Gyar RT
Priority to AT89900294T priority Critical patent/ATE103279T1/en
Publication of EP0393109A1 publication Critical patent/EP0393109A1/en
Application granted granted Critical
Publication of EP0393109B1 publication Critical patent/EP0393109B1/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/12—1,4-Thiazines; Hydrogenated 1,4-thiazines not condensed with other rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

  • This invention relates to novel 2 ,3-thiomorpolinedione-2-oxime-derivatives of the general formula (I),
  • R 1 stands for hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy or nitro group
  • R 2 e ans a C 1-7 alkyl group optionally substituted by: hydroxyl or oxo group; or an ester group containing 1 to 4 carbon atoms in the alkoxy moiety; or a C 1-4 alkoxy. cyano, amino, C 1-4 alkylamino, or dialkylamino group; or an acyl group containing 1 to 7 carbon atoms in the alkyl moiety; or R 2 means an aryl-C 1-7 alkyl group optionally bearing the substituents defined above for R 2 in the alkyl chain and optionally substituted by halogen, nitro, C 1-4 alkyl or alkoxy group in the benzene ring; or R 2 represents an allyl, phenylallyl or phenylsulfonyl group, both latter groups optionally being substituted by halogen or a C 1-4 alkyl group in the benzene ring; or R 2 stands for a carbamoyl group substituted by one or two C
  • the compounds of the general formula (I) have interesting cytoprotective and gastric acid secretion-inhibiting properties and are effective against gastric and duodenal ulcers.
  • the aim of the present invention was to find novel, therapeutically useful compounds which can be prepared economically on an industrial scale, too. Accordingly the invention relates also to a process for the preparation of the new compounds of general formula (I),
  • R 1 stands for hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy or nitro group
  • R 2 means a C 1 _ 7 alkyl group optionally substituted by: a hydroxyl or oxo group; or an ester group containing 1 to 4 carbon atoms in the alkoxy moiety; or a C 1-4 alkoxy, cyano, amino, C 1-4 alkylamino, or dialkylamino group; or an acyl group containing 1 to 7 carbon atoms in the alkyl moiety; or
  • R 2 means an aryl-C 1-7 alkyl group optionally bearing the substituents defined above for R 2 in the alkyl chain and optionally substituted by halogen, nitro, C 1-4 alkyl or alkoxy group in the benzene ring; or
  • R 2 represents an allyl, phenylallyl or phenylsulfonyl group, both latter groups optionally being substituted by halogen or a C 1-4 alkyl group in the benzene ring; or
  • R 2 stands for a carbamoyl group substituted by one or two C 1-4 alkyl group(s) or phenyl group on the nitrogen atom which comprises a ) to obtain compoun ds of the gener a l f ormu l a (I) containing as R 2 a substituent different from an N ⁇
  • R 3 has the same meaning as R 2 , except the N-substituted carbamoyl group and X is halogen or, when the meaning of R 3 is different from an acylatable group, X may be also a mesyloxy or tosyloxy group; or b) to obtain compounds of the general formula (I) containing an N-substituted cabamoyl group as R 2 , reacting a compound of the general formula (II), wherein R 1 is as defined above, in an inert organic solvent in the presence of an organic tertiary amine, preferably triethylamine with a compound of the general formula (IV), R 4 - NCO
  • R 4 stands for a phenyl or C 1-4 alkyl group.
  • the compounds according to the present invention can be prepared by the methods discussed hereinafter: a) a substitution alkylation or acylation is carried out the using a compound of the general formula (III), wherein R 3 is the same as R 2 , except any N-substituted cabamoyl group; and b) an addition acylation is performed by using a compound of the general formula (IV); in this case R 2 stands for an N-substituted cabamoyl group.
  • the reaction is usually carried out in an organic solvent, preferably in methanol, ethanol, acetone or in an ether-type solvent, such as dioxane; or in acetonitrile, dimethylformamide or dimethylsulfoxide.
  • organic solvent preferably in methanol, ethanol, acetone or in an ether-type solvent, such as dioxane; or in acetonitrile, dimethylformamide or dimethylsulfoxide.
  • Alkaline metal hydroxides, carbonates, alkoxides or organic bases such as tertiary amines may be used as acid binding agents.
  • the reaction is usually carried out at a temperature corresponding to the boiling point of the solvent used. After filtering off the precipitated salt, the product is isolated by evaporating the reaction mixture and then purified by a method known per se.
  • Suitable catalysts are organic tertiary amine bases, preferably triethylamine.
  • the reaction temperature may be varied between 0 °C and 100 °C.
  • 4-phenylmethyl-0-methyl-2,3-thiomorpholinedione-2-oxime exerts a particularly advantageous effect based on the pharmacological inventigations.
  • This compound shows a gastric acid secretion-inhibiting action with an oral ED 50 value of 20 mg/kg in the so-called Shay's rats, is effective also against stress-induced ulcers with an oral ED 50 value of 71 mg/kg and against acidic ethanol-induced gastric ulcers with an oral ED 50 value of 7 mg/kg.
  • Example 1 General Example for the substitution alkylation or acylation, respectively

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Indole Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

La présente invention se rapporte à de nouveaux composés représentés par la formule générale (I), où R1 représente un groupe hydrogène, halogène, C1-4 alkyle, C1-4 alkoxy ou nitro; R2 représente un groupe C1-7 alkyle éventuellement substitué par: un groupe hydroxyle ou oxo; ou un groupe ester contenant 1 à 4 atomes de carbone dans la fraction alkoxy; ou un groupe C1-4 alkoxy, cyano, amino, C1-4 alkylamino ou dialkylamino; ou un groupe acyle contenant 1 à 7 atomes de carbone dans la fraction alkyle; ou R2 représente un groupe aryl-C1-7 alkyle portant éventuellement les substituants définis ci-dessus pour R2 dans la chaîne alkyle et éventuellement substitué par un groupe halogène, nitro, C1-4 alkyle ou alkoxy dans l'anneau de benzène; ou R2 représente un groupe allyle, phénylallyle ou phénylsulfonyle, ces deux derniers groupes étant éventuellememt substitués par un halogène ou par un groupe C1-4 alkyle dans l'anneau de benzène; ou R2 représente un groupe carbamoyle substitué par un ou deux groupe(s) C1-4 alkyle ou par un groupe phényle sur l'atome d'azote. Les composés de la présente invention exercent une action cytoprotectrice et d'inhibition de la sécrétion d'acide et sont par conséquent efficaces contre les ulcères gastriques et duodénaux.The present invention relates to new compounds represented by the general formula (I), where R1 represents a hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy or nitro group; R2 represents a C1-7 alkyl group optionally substituted by: a hydroxyl or oxo group; or an ester group containing 1 to 4 carbon atoms in the alkoxy moiety; or a C1-4 alkoxy, cyano, amino, C1-4 alkylamino or dialkylamino group; or an acyl group containing 1 to 7 carbon atoms in the alkyl moiety; or R2 represents an aryl-C1-7 alkyl group optionally carrying the substituents defined above for R2 in the alkyl chain and optionally substituted by a halogen, nitro, C1-4 alkyl or alkoxy group in the benzene ring; or R2 represents an allyl, phenylallyl or phenylsulfonyl group, the latter two groups being optionally substituted by a halogen or by a C1-4 alkyl group in the benzene ring; or R2 represents a carbamoyl group substituted by one or two C1-4 alkyl group (s) or by a phenyl group on the nitrogen atom. The compounds of the present invention exert a cytoprotective and inhibitory action on acid secretion and are therefore effective against gastric and duodenal ulcers.

Description

NOVEL 2,3-THIOMORPHOLINEDIONE-2-OXIME DERIVATIVES, PHARMACEUTICAL COMPOSITIONS CONTAINING Th'EM AND PROCESS FOR PREPARING SAME
This invention relates to novel 2 ,3-thiomorpolinedione-2-oxime-derivatives of the general formula (I),
wherein
R1 stands for hydrogen, halogen, C1-4alkyl, C1-4alkoxy or nitro group;
R2 eans a C1-7alkyl group optionally substituted by: hydroxyl or oxo group; or an ester group containing 1 to 4 carbon atoms in the alkoxy moiety; or a C1-4 alkoxy. cyano, amino, C1-4 alkylamino, or dialkylamino group; or an acyl group containing 1 to 7 carbon atoms in the alkyl moiety; or R 2 means an aryl-C1-7alkyl group optionally bearing the substituents defined above for R2 in the alkyl chain and optionally substituted by halogen, nitro, C1-4alkyl or alkoxy group in the benzene ring; or R2 represents an allyl, phenylallyl or phenylsulfonyl group, both latter groups optionally being substituted by halogen or a C1-4alkyl group in the benzene ring; or R2 stands for a carbamoyl group substituted by one or two C1-4alkyl group(s) or phenyl group on the nitrogen atom as well as the pharmaceutical compositions containing these compounds.
The compounds of the general formula (I) have interesting cytoprotective and gastric acid secretion-inhibiting properties and are effective against gastric and duodenal ulcers.
The therapeutic importance of the above new compounds is very high since the number of patients suffering from gastric and duodenal ulcer is continuously increasing both in the absolute and relative sense as well. Although a number of drugs are known which are useful for the ulcer therapy, no similar effect has up to the present been described for 2,3-thiomorpholinedione-2-oximes. According to the literature, several patents
(United States patent specifications Nos. 3,790,566, 3,883,510, 3,894,150, 3,930,002, 4,003,895 and 4,003,897) describing 2,3-thiomorpholinedione-2-oxime derivatives .as pesticides were granted for the Union Carbide and the du Pont companies; however, no benzyl group substituted by R1 was bound to the ring nitrogen in the compounds of these patents.
Thus, the aim of the present invention was to find novel, therapeutically useful compounds which can be prepared economically on an industrial scale, too. Accordingly the invention relates also to a process for the preparation of the new compounds of general formula (I),
wherein
R1 stands for hydrogen, halogen, C1-4alkyl, C1-4alkoxy or nitro group;
R2 means a C1_7alkyl group optionally substituted by: a hydroxyl or oxo group; or an ester group containing 1 to 4 carbon atoms in the alkoxy moiety; or a C1-4alkoxy, cyano, amino, C1-4alkylamino, or dialkylamino group; or an acyl group containing 1 to 7 carbon atoms in the alkyl moiety; or
R2 means an aryl-C1-7alkyl group optionally bearing the substituents defined above for R2 in the alkyl chain and optionally substituted by halogen, nitro, C1-4alkyl or alkoxy group in the benzene ring; or
R2 represents an allyl, phenylallyl or phenylsulfonyl group, both latter groups optionally being substituted by halogen or a C1-4alkyl group in the benzene ring; or
R2 stands for a carbamoyl group substituted by one or two C1-4alkyl group(s) or phenyl group on the nitrogen atom which comprises a ) to obtain compoun ds of the gener a l f ormu l a (I) containing as R2 a substituent different from an N¬
-substituted carbamoyl group reacting a compound of the general formula (II), wherein R1 is as defined above, in an inert organic solvent in the presence of an inorganic or organic base with a compound of the general formula (III),
R3—X
(III) wherein R3 has the same meaning as R2, except the N-substituted carbamoyl group and X is halogen or, when the meaning of R3 is different from an acylatable group, X may be also a mesyloxy or tosyloxy group; or b) to obtain compounds of the general formula (I) containing an N-substituted cabamoyl group as R2, reacting a compound of the general formula (II), wherein R1 is as defined above, in an inert organic solvent in the presence of an organic tertiary amine, preferably triethylamine with a compound of the general formula (IV), R4 - NCO
(IV) wherein R4 stands for a phenyl or C1-4alkyl group.
The preparation of the 2,3-thiomorpholinedione-2-oxime derivatives of general formula (II) used as starting substances has been described in our patent application simultaneously filed. According to those reported in that patent application, the compounds of the general formula (II) can be prepared e.g. by reacting an appropriately substituted 2-nitromethylene-3-(phenylmethyl)thiazolidine with a basic reagent in an aqueous and/or alcoholic medium.
From the 2,3-thiomorpholinedione-2-oxime derivatives of the general formula (II), the compounds according to the present invention can be prepared by the methods discussed hereinafter: a) a substitution alkylation or acylation is carried out the using a compound of the general formula (III), wherein R3 is the same as R2, except any N-substituted cabamoyl group; and b) an addition acylation is performed by using a compound of the general formula (IV); in this case R2 stands for an N-substituted cabamoyl group.
In the process variant a) of the present invention, the reaction is usually carried out in an organic solvent, preferably in methanol, ethanol, acetone or in an ether-type solvent, such as dioxane; or in acetonitrile, dimethylformamide or dimethylsulfoxide. Alkaline metal hydroxides, carbonates, alkoxides or organic bases such as tertiary amines may be used as acid binding agents. The reaction is usually carried out at a temperature corresponding to the boiling point of the solvent used. After filtering off the precipitated salt, the product is isolated by evaporating the reaction mixture and then purified by a method known per se.
When using process variant b) of the invention, the reaction is accomplished in the presence of a solvent and a catalyst. Depending on the solubility conditions of the reactants used, C3-6ketones,
C2-5ethers, dimethylformamide, dimethylsulfoxide, C5-10hydrocarbons or chlorinated hydrocarbons may preferebly be employed as solvents. Suitable catalysts are organic tertiary amine bases, preferably triethylamine. The reaction temperature may be varied between 0 °C and 100 °C.
Out of the compounds of the general formula (I), 4-phenylmethyl-0-methyl-2,3-thiomorpholinedione-2-oxime exerts a particularly advantageous effect based on the pharmacological inventigations. This compound shows a gastric acid secretion-inhibiting action with an oral ED50 value of 20 mg/kg in the so-called Shay's rats, is effective also against stress-induced ulcers with an oral ED50 value of 71 mg/kg and against acidic ethanol-induced gastric ulcers with an oral ED50 value of 7 mg/kg.
The invention is illustrated in detail by the following non-limiting Examples. Example 1 General Example for the substitution alkylation or acylation, respectively
After weighing 100 mmol of a compound of the general formula (II), 20 ml of acetone, 10 mmol of a compound of the general formula (III), 10 mmol of potassium carbonate and 1 mmol of potassium iodide in a round-bottom flask, the reaction mixture is refluxed until the substance of general formula (II) as detected by thin layer chcmatograhy (TLC) diappears, then the inorganic precipitate is filtered off and the filtrate is evaporated. The residue is purified after having been solidified by adding ether by recrystallisation or by column chomatography. The data of compounds obtained by this method are summarized in Table I. Chemical names of the compounds listed in Table I: 1. 4-Phenylmethyl-0-phenylmethyl-2,3-thiomorpholinedione-2-oxime
2. 4-Phenylmethyl-0-ethoxycarbonylmethyl-2,3-thiomorpholinedione-2-oxime
3. 4-Phenylmethyl-0-methyl-2,3-thiomorpholinedione-2-oxime
4. 4-Phenylmethyl-0-ethyl-2,3-thiomorpholinedione-2-oxime
5. 4-Phenylmethyl-0-n-propyl-2,3-thiomorpholine-dione-2-oxime 6 . 4-Phenylmethyl-0-(3-phenyl-1-propyl)-2,3- thiomorpholinedione-2-oxime
7. 4-Phenylmethyl-0-cyanomethyl-2,3-thiomorpholinedione-2-oxime
8. 4-(2-Chlorophenylmethyl)-0-methyl-2,3-thiomorpholinedione-2-oxime
9. 4-(4-Methoxyphenylmethyl)-0-methyl-2,3-thiomorpholinedione-2-oxime
10. 4-(3-Chlorophenylmethyl)-0-methyl-2,3-thiomorpholinedione-2-oxime 11. 4-(4-Methylphenylmethyl)-0-methyl-2,3-thiomorpholinedione-2-oxime
12. 4-Phenylmethyl-0-cinnamyl-2,3-thiomorpholinedione-2-oxime
13. 4-Phenylmethyl-0-tosyl-2,3-thiomorpholinedione-2-oxime
14. 4-Phenylmethy1-0-phenylsulfony1-2,3-thiomorpholinedione-2-oxime
15. 4-Phenylmethyl-0-(4-fluorphenylsulfonyl)-2,3- thiomorpholinedione-2-oxime 16. 4-Phenylmethyl-0-dimethylcarbamoyl-2,3-thiomorpholinedione-2-oxime 17. 4-Phenylmethyl-0-(3-hydroxy-1-propyl)-2,3-thiomorpholinedione-2-oxime Example 2 General Example for the addition acylation After weighing 10 mmol of the compound of general formula (I), 20 ml of acetone, 15 mmol of triethylamine and 11 mmol of the substance of general formula (IV) in a round-bottom flask, the reaction mixture is stirred at room temperature for 24 hours, then the unreacted compound of the general formula (II) is filtered off and the filtrate is evaporated. The residue is purified after having been solidified by adding ether and then by recrystallisation or by direct chromatography. The data of compounds obtained by this method are summarized in Table II.
Chemical names of the compounds listed in Table
1. 4-Phenylmethyl-0-n-butylcarbamoyl-2,3-thiomorpholinedione-2-oxime
2. 4-Phenylmethyl-0-phenylcarbamoyl-2,3-thiomorpholinedione-2-oxime
3. 4-Phenylmethyl-0-ethylcarbamoyl-2,3-thiomorpholinedione-2-oxime Example 3
Preparation of 4-phenylmethyl-2,3-thiomorpholinedione-2-oxime
2,36 g (0.01 mol) of 3-phenylmethyl-2-nitromethylenethiazolidine are boiled under reflux in the mixture of 50 ml of IN sodium hydroxide solution and 25 ml of ethanol until the dissolution of the starting substance (when, based on the TLC examination, no starting substance is detected in a sample taken from the reaction mixture). Then, the mixture is cooled, acidified by adding hydrochloric acid diluted to 1:1 with water (to a pH value of 1), the precipitated product is filtered off, washed with water and dried to give the title compound in a yield of 2,15 g (91%), m.p.: 225-227 °C. The purity of this product is 99.7% when measured by titration with alkaline metal hydroxide in pyridine, in the presence of silver nitrate.
O

Claims

Claims
1 , 2 , 3-Thiomorpholinedione-2-oxime derivatives of the general f ormula (I ) ,
wherein
R1 stands for hydrogen, halogen, C1-4alkyl, C1-4alkoxy or nitro group;
R2 means a C1-4alkyl group optionally substituted by: a hydroxyl or oxo group; or an ester group containing 1 to 4 carbon atoms in the alkoxy moiety; or a C1-4alkoxy, cyano, amino, C1-4alkylamino, or dialkylamino group; or an acyl group containing 1 to 7 carbon atoms in the alkyl moiety; or
R2 means an aryl-C1-4alkyl group optionally bearing the substituents defined above for R2 in the alkyl chain and optionally substituted by halogen, nitro, C1-4alkyl or alkoxy group in the benzene ring; or
R2 represents an allyl, phenylallyl or phenylsulfonyl group, both latter groups optionally being substituted by halogen or a C1-4alkyl group in the benzene ring; or
R2 stands for a carbamoyl group substituted by one or two C1-4alkyl group(s) or phenyl group on the nitrogen atom.
2. 4-Phenylmethyl-0-methyl-2,3-thiomorpholinedione--2-oxime.
3. A process for the preparation of 2,3-thiomorpholinedione-2-oxime derivatives of the general formula (I),
wherein
R1 stands for hydrogen, halogen, C1-4alkyl, C1-4alkoxy or nitro group;
R2 means a C1-4alkyl group optionally substituted by: a hydroxyl or oxo group; or an ester group containing 1 to 4 carbon atoms in the alkoxy moiety; or a C1-4alkoxy, cyano, amino, C1-4alkylamino, or dialkylamino group; or an acyl group containing 1 to 7 carbon atoms in the alkyl moiety; or
R2 means an aryl-C1-4alkyl group optionally bearing the substitueπts defined above for R2 in the alkyl chain and optionally substituted by halogen, nitro, C alkyl or alkoxy group in the benzene ring; or
R2 represents an allyl, phenylallyl or phenylsulfonyl group, both latter groups optionally being substituted by halogen or a C1-4alkyl group in the benzene ring; or
R2 stands for a carbamoyl group substituted by one or two C1-4alkyl group(s) or phenyl group on the nitrogen atom which comprises a) to obtain compounds of the general formula (I) containing as R2 a substituent different from an N¬
-substituted carbamoyl group, reacting a compound of the general formula (II), wherein R1 is as defined above, in an inert organic solvent in the presence of an inorganic or organic base with a compound of the general formula (III),
R3-X
(III)
wherein R3 has the same meaning as R2, except the N-substituted carbamoyl group and X is halogen or, when the meaning of R3 is different from an acylatable group, X may be also a mesyloxy or tosyloxy group; or b) to obtain compounds of the general formula (I) containing an N-substituted cabamoyl group as R2, reacting a compound of the general formula (II), wherein R1 is as defined above, in an inert organic solvent in the presence of an organic tertiary amine, preferebly triethylamine with a compound of the general formula (IV),
R4-NCO (IV)
wherein R4 stands for a phenyl or C1-4alkyl group.
4. A process as claimed in claim 3 a) which comprises carrying out the reaction at about a temperature of the boiling point of the solvent used
5. A process as claimed in claim 3 a), which comprises using an alkaline metal hydroxide, carbonate or alkoxide or a C1-4alkylamine, preferably a tertiery amine as an inorganic or organic base, respectively.
6. A process as claimed in claim 3 b), which comprises carrying out the reaction at a temperature between 0 °C and 100 °C.
7. A process as claimed in claim 3 a) which comprises using a C1-4alcohol, C3-6 ketone, C2-5 ether or acetonitrile, dimethylsulfoxide or dimethylformamide as an inert organic solvent.
8. A process as claimed in claim 3 b), which comprises using a C3-6 ketone, C2-5 ether, acetonitrile, dimethylsulfoxide, dimethylformamide, C5-10 hydrocarbon or chlorinated hydrocarbon as an inert organic solvent.
9. A pharmaceutical composition, which comprises as active ingredient a 2,3-thiomorpholinedione-2-oxime derivative of the general formula (I),
wherein
R1 stands for hydrogen, halogen C1-4alkyl, C1-4alkoxy or nitro group;
R2 means a C1-7alkyl group optionally substituted by: a hydroxyl or oxo group; or an ester group containing 1 to 4 carbon atoms in the alkoxy moiety; or a C1-4alkoxy, cyano, amino, C1-4alkylamino, or dialkylamino group; or an acyl group containing 1 to 7 carbon atoms in the alkyl moiety; or means an aryl-C1-7 a lkyl group optionally bearing the substituents defined above for R2 in the alkyl chain and optionally substituted by halogen, nitro, C1-4alkyl or alkoxy group in the benzene ring; or R2 represents an allyl, phenylallyl or phenylsulfonyl group, both latter groups optionally being substituted by halogen or a C1-4alkyl group in the benzene ring; or R2 stands for a carbamoyl group substituted by one or two C1-4alkyl group(s) or phenyl group on the nitrogen atom in admixture with carriers and/or additives commonly used in the pharmaceutical industry.
10. A process for the preparation of a pharmaceutical composition, which comprises mixing as active ingredient a 2,3-thiomorpholinedione-2-oxime derivative of the general formula (I), wherein R1, and R2 are as defined in claim 3, prepared by using a process according to claim 3 with carriers and/or additives commonly used in the pharmaceutical industry and transforming them to a pharmaceutical composition.
EP89900294A 1987-12-14 1989-07-05 Novel 2,3-thiomorpholinedione-2-oxime derivatives, pharmaceutical compositions containing them and process for preparing same Expired - Lifetime EP0393109B1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT89900294T ATE103279T1 (en) 1987-12-14 1989-07-05 2,3-THIOMORPHOLINEDIONE-2-OXIME DERIVATIVES, MEDICINAL COMPOSITIONS AND METHOD OF MANUFACTURE.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HU563087 1987-12-14
HU875630A HU199134B (en) 1987-12-14 1987-12-14 Process for producing new 2,3-thiomorpholinedine-2-oxime derivatives and pharmaceutical compositions comprising same

Publications (2)

Publication Number Publication Date
EP0393109A1 true EP0393109A1 (en) 1990-10-24
EP0393109B1 EP0393109B1 (en) 1994-03-23

Family

ID=10970505

Family Applications (1)

Application Number Title Priority Date Filing Date
EP89900294A Expired - Lifetime EP0393109B1 (en) 1987-12-14 1989-07-05 Novel 2,3-thiomorpholinedione-2-oxime derivatives, pharmaceutical compositions containing them and process for preparing same

Country Status (8)

Country Link
US (1) US5106846A (en)
EP (1) EP0393109B1 (en)
JP (1) JPH03502688A (en)
KR (1) KR920009884B1 (en)
CN (1) CN1016689B (en)
DE (1) DE3888697T2 (en)
HU (1) HU199134B (en)
WO (1) WO1989005805A1 (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
UA56185C2 (en) 1996-09-30 2003-05-15 Пфайзер Інк. Aralkyl- and aralkylidene heterocyclic lactams and imids, a pharmaceutical composition and a treatment method
US6423708B1 (en) 1996-09-30 2002-07-23 Pfizer Inc Aralkyl and aralkylidene heterocyclic lactams and imides
EP2668156B1 (en) 2011-01-28 2018-10-31 Basf Se Polymerizable composition comprising an oxime sulfonate as thermal curing agent

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3790566A (en) * 1971-08-12 1974-02-05 Du Pont Carbamate esters of 2-oxyimino-3-keto-1,4-diheterocyclics
US3883510A (en) * 1971-08-12 1975-05-13 Du Pont Carbamate esters of 2-oxyimino-3-keto-1,4-diheterocyclics
US4003895A (en) * 1972-12-29 1977-01-18 Union Carbide Corporation 1,4-Thiazines
US3930002A (en) * 1972-12-29 1975-12-30 Jr John Apling Durden Carbamate pesticidal compositions
US3894150A (en) * 1972-12-29 1975-07-08 Union Carbide Corp Carbamate pesticidal compositions
US4003897A (en) * 1974-06-07 1977-01-18 Union Carbide Corporation Carbamate pesticidal compounds
US4327110A (en) * 1977-03-28 1982-04-27 Union Carbide Corporation Pesticidal symmetrical N-substituted bis-carbamoyloximino disulfide compounds
JPS61113437A (en) * 1984-09-11 1986-05-31 ゼテク・インコ−ポレ−テツド Method and apparatus for foreknowing ovulation of woman

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8905805A1 *

Also Published As

Publication number Publication date
EP0393109B1 (en) 1994-03-23
WO1989005805A1 (en) 1989-06-29
KR900700471A (en) 1990-08-13
HU199134B (en) 1990-01-29
KR920009884B1 (en) 1992-11-05
US5106846A (en) 1992-04-21
HUT49127A (en) 1989-08-28
DE3888697D1 (en) 1994-04-28
CN1016689B (en) 1992-05-20
DE3888697T2 (en) 1994-07-07
JPH03502688A (en) 1991-06-20
CN1034927A (en) 1989-08-23

Similar Documents

Publication Publication Date Title
EP0061149B1 (en) Alkylenedioxybenzene derivatives and acid addition salts thereof and a process for their preparation
CA2368815A1 (en) Novel synthesis and crystallization of piperazine ring-containing compounds
US5120736A (en) 4-methyl-5-(2-(4-phenylpiperazin-1-yl)ethyl)thiazole derivatives their method of preparation and the pharmaceutical compositions in which they are present
CH661507A5 (en) DERIVATIVES OF HYDROXYMETHYL-5 OXAZOLIDINONE-2 N-ARYLATED AND THEIR PREPARATION PROCESS.
US4297357A (en) N-Phenethylacetamide compounds and process for preparation thereof
EP0393109B1 (en) Novel 2,3-thiomorpholinedione-2-oxime derivatives, pharmaceutical compositions containing them and process for preparing same
US4075409A (en) Benzophenone derivatives
EP0320910B1 (en) 2-Thiazolidinone derivatives, pharmaceutical compositions containing them, process for preparing same, and use
EP0220653A2 (en) 3-Aminocarbonyl-1,4-dihydropyridine-5-carboxylic acid compounds, process for preparation and use thereof, and pharmaceutical composition containing the same
EP0233760A1 (en) Sulfenamide derivatives and their production
US5169859A (en) Thiazolidinone derivatives, pharmaceutical compositions containing them and process for preparing same
Laliberté et al. Synthesis of new chalcone analogues and derivatives
US4121036A (en) 3-Amino-2-Hydrazinopyridine derivatives
US4002620A (en) 2-Anilino-4H-3,1-benzothiazines
KR880000154B1 (en) The method of preparation for amino-nitro pyridine
US3187002A (en) Hs-chxcook
RU2032681C1 (en) Method for production of 1-{2-[(5-dimethylaminomethyl-2-furyl)-methylthio] -ethyl}-amino-1-methyl- -amino-2-nitroethylene
JP2004511548A (en) Method for preparing N-substituted 2-sulfanilimidazole
CZ357190A3 (en) Dihydropyrimidothiazine derivatives, process of their preparation and pharmaceutical compositions containing thereof
US4195179A (en) 5-(Indol-3-ylmethylene)-1,3-dimethyl-2-methylamino-4-imidazolidinone
JPS5931512B2 (en) Method for producing triazolobenzazepine derivatives
US3121716A (en) Pyrazinamide and derivatives thereof
KR800001551B1 (en) Preparing process for cyclic compounds
EP0412014A1 (en) Benzothiazine derivatives, their preparation and their uses as medicines or as intermediates for the synthesis of medicines
JPH06228103A (en) New octahydroacridine derivative and its production

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19900526

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE FR GB IT LI LU NL SE

17Q First examination report despatched

Effective date: 19920706

ITF It: translation for a ep patent filed

Owner name: INTERPATENT ST.TECN. BREV.

ITTA It: last paid annual fee
GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE CH DE FR GB IT LI LU NL SE

REF Corresponds to:

Ref document number: 103279

Country of ref document: AT

Date of ref document: 19940415

Kind code of ref document: T

REF Corresponds to:

Ref document number: 3888697

Country of ref document: DE

Date of ref document: 19940428

ET Fr: translation filed
PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SE

Payment date: 19941129

Year of fee payment: 7

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 19941209

Year of fee payment: 7

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: AT

Payment date: 19941220

Year of fee payment: 7

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 19941223

Year of fee payment: 7

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CH

Payment date: 19941227

Year of fee payment: 7

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: BE

Payment date: 19941228

Year of fee payment: 7

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19941231

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: NL

Payment date: 19941231

Year of fee payment: 7

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

EAL Se: european patent in force in sweden

Ref document number: 89900294.3

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 19950228

Year of fee payment: 7

26N No opposition filed
PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Effective date: 19951213

Ref country code: AT

Effective date: 19951213

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Effective date: 19951214

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LI

Effective date: 19951231

Ref country code: CH

Effective date: 19951231

Ref country code: BE

Effective date: 19951231

BERE Be: lapsed

Owner name: RICHTER GEDEON VEGYESZETI GYAR R.T.

Effective date: 19951231

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Effective date: 19960701

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 19951213

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Effective date: 19960830

NLV4 Nl: lapsed or anulled due to non-payment of the annual fee

Effective date: 19960701

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Effective date: 19960903

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20051213